Throughout this application, various publications are referenced by author and date within the text. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding the claims. All patents, patent applications and publications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
It has long been hypothesized that ischemia primes mechanisms leading to reperfusion injury and sets the stage for an exaggerated, maladaptive vascular response eventuating in tissue damage. Hypoxemia, a central component of the ischemic vascular milieu, has been defined as a key factor initiating vascular injury. To date, the cellular response to oxygen deprivation has largely been defined by studies of the transcription factor HIF (Hypoxia-Inducible Factor)-1. Activation of HIF-1 by hypoxia/hypoxemia facilitates metabolic adaptation to environmental challenge; glucose uptake by the noninsulin-dependent glucose transporter (GLUT1) is enhanced, and expression of glycolytic enzymes, erythropoietin and Vascular Endothelial Growth Factor (VEGF) is amplified. However, another facet of the cellular response to hypoxia has been revealed by the deposition of fibrin in lung vasculature consequent to induction of procoagulant tissue factor.